Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ib alpha, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb alpha interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 mu g/kg, n=6; 500 mu g/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105 34 and 156 +/- 23 (p < 0.05) min, respectively compared to the saline treated control group (32 +/- 6 min, n=6). Patency of the injured vessel was sustained in 1/6 (100 mu g/kg) and 3/6 vessels (500 mu g/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 mu g/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day -2 followed by 1.1 mg/kg daily for 2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2 +/- 30.0 min and 136.1 +/- 39.5 min (p < 0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 mu g/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4 +/- 35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 mu g/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (73.5 +/- 32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.
